Although their pathologic function in defense against neoplasia is yet incompletely understood, macrophages probably play a significant part in the rejection of tumors. Of importance to immunotherapy, this role can be augmented by immunostimulants. We hypothesize effective macrophage cytotoxicity requires altering their metabolism (activation) and equipping them with surface recognition factors specific for the target cells (education). In a quantitative assay of macrophage cytotoxicity developed in this laboratory, we propose to test the above hypothesis by measuring the cytotoxicity of murine macrophages toward syngeneic tumors induced by methyl cholanthrene. The cytotoxicity of variously activated macrophages will be determined and compared with that of variously educated macrophages. The studies will probe the relationship between activation and education, how these affect cytotoxicity, and the cytotoxic specificity of the altered cells. The studies seek to define the properties of activation that confer heightened cytotoxicity and the mechanism of the cytotoxicity. Factors including mode of activation and role of cyclic nucleotides that regulate the cytotoxicity of activation will be studied. Emphasis will be placed on seeking drugs that can pharmacologically increase macrophage cytotoxicity. The long range strategy is to define simple means of activating and educating macrophages, that can induce effective cytotoxicity in vitro and ultimately in vivo. The ultimate goal is development of a rational basis of immunotherapy that employs either simplified stimulants of macrophage function or infusions of macrophages altered for effective cytotoxicity.